Protein kinases are involved in the signal transduction pathways linking growth factors, hormones and other cell regulation molecules to cell growth, survival and metabolism under both normal and pathological conditions. One such protein kinase, protein kinase B (also known as Akt), is a serine/threonine kinase that plays a central role in promoting the proliferation and survival of a wide range of cell types, thereby protecting cells from apoptosis (programmed cell death).
A number of protein kinases and phosphatases regulate the activity of Akt. For instance, activation of Akt is mediated by phosphatidylinositol 3-kinase (PI3-K), which initiates the binding of second messenger phospholipids to the pleckstrin homology (PH) binding domain of Akt. The binding anchors Akt to plasma membrane and results in phosphorylation and activation of the enzyme. Amplifications of the catalytic subunit of PI3-K, p110α, or mutations in the PI3-K regulatory subunit, p85α, lead to activation of Akt in several types of human cancer. Recent studies have also demonstrated the role of the PI3-K/AKT pathway in the life cycle of numerous viruses.
WO 01/91754 pertains to protein kinase inhibitors. WO 2005/011697 involves protein kinase A and B inhibitors. WO 2005/054202 pertains to AKT inhibitors.
Because of its pivotal role in the regulation of cell survival, Akt provides a novel therapeutic target for the effective treatment of various disorders, particularly cancer and viral infections. However, such treatment requires the development of potent, selective, bioavailable inhibitors of Akt. A need exists for alternative Akt inhibitors. Thus, the present invention provides novel inhibitors of Akt that exhibit increased potency, selectivity, and/or bioavailability, compositions comprising these compounds, and methods of using these compounds.
Additionally, pharmaceutical compositions containing novel inhibitors of Akt when diluted or in solution necessarily must be free from precipitation in order to be delivered to a patient. The present invention provides pharmaceutical compositions comprising novel Akt inhibitors at particular pH ranges that lack such precipitation.